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Objective: To analyse if the health progression of geriatric Covid-19 survivors three months after an acute Covid-19 infection was worse than in other geriatric patients. Specifically, we wanted to see if we could see distinct health profiles in the flow of re-admitted Covid-19 patients compared to re-admitted non-Covid-19 controls. Design: Matched cohort study. Setting and participants: Electronic medical records of geriatric patients hospitalised in geriatric clinics in Stockholm, Sweden, between March 2020 and January 2022. Patients readmitted three months after initial admission were selected for the analysis and Covid-19 survivors (n = 895) were compared to age-sex-Charlson comorbidity index (CCI)-matched non-Covid-19 controls (n = 2685). Methods: We assessed using binary logistic and Cox regression if a previous Covid-19 infection could be a risk factor for worse health progression indicated by the CCI, hospital frailty risk score (HFRS), mortality and specific comorbidities. Results: The patients were mostly older than 75 years and, already at baseline, had typically multiple comorbidities. The Covid-19 patients with readmission had mostly had their acute-phase infection in the 1st or 2nd pandemic waves before the vaccinations. The Covid-19 patients did not have worse health after three months compared to the matched controls according to the CCI (odds ratio, OR[95% confidence interval, CI] = 1.12[0.94–1.34]), HFRS (OR[95%CI] = 1.05[0.87–1.26]), 6-months (hazard ratio, HR[95%CI] = 1.04[0.70–1.52]) and 1-year-mortality risk (HR[95%CI] = 0.89[0.71–1.10]), adjusted for age, sex and health at baseline (the CCI and HFRS). Conclusions and implications: The overall health progression of re-hospitalized geriatric Covid-19 survivors did not differ dramatically from other re-hospitalized geriatric patients with similar age, sex and health at baseline. Our results emphasize that Covid-19 was especially detrimental for geriatric patients in the acute-phase, but not in the later phase. Further studies including post-vaccination samples are needed. [ABSTRACT FROM AUTHOR]

In the present work, a novel infrared-assisted extraction coupled to headspace solid-phase microextraction (IRAE-HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS) was developed for rapid determination of the volatile components in green tea. The extraction parameters such as fiber type, sample amount, infrared power, extraction time, and infrared lamp distance were optimized by orthogonal experimental design. Under optimum conditions, a total of 82 volatile compounds in 21 green tea samples from different geographical origins were identified. Compared with classical water-bath heating, the proposed technique has remarkable advantages of considerably reducing the analytical time and high efficiency. In addition, an effective classification of green teas based on their volatile profiles was achieved by partial least square-discriminant analysis (PLS-DA) and hierarchical clustering analysis (HCA). Furthermore, the application of a dual criterion based on the variable importance in the projection (VIP) values of the PLS-DA models and on the category from one-way univariate analysis (ANOVA) allowed the identification of 12 potential volatile markers, which were considered to make the most important contribution to the discrimination of the samples. The results suggest that IRAE-HS-SPME/GC-MS technique combined with multivariate analysis offers a valuable tool to assess geographical traceability of different tea varieties. [ABSTRACT FROM AUTHOR]

Objective: To investigate the protective effect of chitosan oligosaccharide (COS) on acute lung injury (ALI) caused by blast injury, and explore possible molecular mechanisms. Methods: A mouse model of blast injury-induced ALI was established using a self-made explosive device. Thirty mice were randomly assigned to control, ALI and ALI + COS groups. An eight-channel physiological monitor was used to determine the mouse physiological index. Enzyme linked immunosorbent assay was used to measure serum inflammatory factors. Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunofluorescence staining, real time-polymerase chain reaction and western blot assay were used to detect inflammatory reactions, oxidative stress and apoptosis. Results: Mice were sacrificed 24 hours after successful model induction. Compared with the ALI group, the heart rate, respiration and PCO2 were significantly lower, but the PO2, TCO2 and HCO3- were significantly higher in the ALI + COS group. Compared to ALI alone, COS treatment of ALI caused a significant decrease in the wet/dry lung weight ratio, indicating a reduction in lung edema, inflammatory cell infiltration, levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-4, IL-6 and nuclear factor kappa B mRNA and protein expression were reduced and IL-10 mRNA and protein expression was increased (P < 0.05). COS significantly inhibited reactive oxygen species, MDA5 and IREα mRNA and protein expressions, cell apoptosis and Bax and Caspase-3 mRNA and protein expressions, and significantly increased superoxide dismutase-1 mRNA expression, and Bcl-2 and Caspase-8 mRNA and protein expression (all P<0.05). COS significantly increased dimethylarginine dimethylaminohydrolase 1 (DDAH1) protein expression, and reduced ADMA and p38 protein expression (P< 0.05). Conclusion: Blast injury causes inflammation, oxidative stress and apoptosis in the lung tissues of mice. COS has protective effects on blast injury-induced ALI, possibly by promoting DDAH1 expression and inhibiting ADMA and mitogen-activated protein kinase pathways. [ABSTRACT FROM AUTHOR]

Objective: Prolactin (PRL) has been reported to be associated with increased bone turnover, and increased bone turnover is also a feature of skeletal fluorosis (SF). Autocrine/paracrine production of PRL is regulated by the extrapituitary promoter and a polymorphism in the extrapituitary PRL promoter at -1149 (rs1341239) is associated with disturbances of bone metabolism in other diseases. Here, we have investigated the possibility that the rs1341239 polymorphism is associated with SF, which results from the consumption of brick tea. Design: We conducted a cross-sectional study in Sinkiang, Qinghai, Inner Mongolia in China. Demography survey questionnaires were completed and physical examination and X-ray diagnoses were used to diagnose SF. Brick tea water fluoride intake (IF) and urinary fluoride (UF) were tested by an F-ion selective electrode method. A Sequenom MassARRAY system was used to determine PRL gene polymorphisms. Results: Subjects who were younger than 45 years of age and carried the T allele had a significantly decreased risk of SF [OR = 0.279 (95%CI, 0.094–0.824)] compared to those carrying the homozygous G allele. This phenomenon was only observed in Kazakh subjects [OR = 0.127 (95%CI, 0.025–0.646)]. Kazakh females who carried T alleles has a decreased risk of SF [OR = 0.410 (95%CI, 0.199–0.847)]. For Kazakh subjects which IF is less than 3.5 mg/d, a decreased risk of SF was observed among the participants who carried T alleles [OR = 0.118 (95%CI, 0.029–0.472)]. Overall, subjects with 1.6–3.2 mg/L UF and carried T alleles had a significantly decreased risk of SF [OR = 0.476 (95%CI, 0.237–0.955)] compared to homozygous G allele carriers. This phenomenon was only observed in Kazakh subjects [OR = 0.324 (95%CI, 0.114–0.923)]. Conclusions: Our results suggested that the PRL rs1341239 T allele decreases the risk of brick tea SF. [ABSTRACT FROM AUTHOR]

The (−)- and (+)-clausenamide (CLA) enantiomers have different pharmacokinetic effects in animals, but their association with putative stereoselective regulation of P-glycoprotein (P-gp) remains unclear. Using three cells expressing P-gp—Caco-2, KBv and rat brain microvessel endothelial cells(RBMEC), this study investigated the association of CLA enantiomers with P-gp. The results showed that the rhodamine 123 (Rh123) accumulation, an indicator of P-gp activity, in Caco-2, KBv and RBMECs was increased by (−)CLA (1 or 5 μmol/L) at 8.2%–28.5%, but reduced by (+)CLA at 11.7%–25.9%, showing stereoselectivity in their regulation of P-gp activity. Following co-treatment of these cells with each CLA enantiomer and verapamil as a P-gp inhibitor, the (+)-isomer clearly antagonized the inhibitory effects of verapamil on P-gp efflux, whereas the (−)-isomer had slightly synergistic or additive effects. When higher concentrations (5 or 10 μmol/L) of CLA enantiomers were added, the stimulatory effects of the (+)-isomer were converted into inhibitory ones, leading to an enhanced intracellular uptake of Rh123 by 24.5%–58.2%; but (−)-isomer kept its inhibition to P-gp activity, causing 30.0%–63.0% increase in the Rh123 uptake. The biphasic effects of (+)CLA were confirmed by CLA uptake in the Caco-2 cells. (+)CLA at 1 μmol/L had significantly lower intracellular uptake than (−)CLA with a ratio[(−)/(+)] of 2.593, which was decreased to 2.167 and 1.893 after CLA concentrations increased to 2.5 and 5 μmol/L. Besides, in the non-induced KB cells, (+)CLA(5 μmol/L) upregulated P-gp expression at 54.5% relative to vehicle control, and decreased Rh123 accumulation by 28.2%, while (−)CLA(5 μmol/L) downregulated P-gp expression at 15.9% and increased Rh123 accumulation by 18.0%. These results suggested that (−)CLA could be a P-gp inhibitor and (+)CLA could be a modulator with concentration-dependent biphasic effects on P-gp activity, which may result in drug—drug interactions when combined with other P-gp substrate drugs. [ABSTRACT FROM AUTHOR]

Beneficial microorganisms (also known as biopesticides) are considered to be one of the most promising methods for more rational and safe crop management practices. We used Bacillus strains EU07, QST713 and FZB24, and investigated their inhibitory effect on Fusarium. Bacterial cell cultures, cell-free supernatants and volatiles displayed varying degrees of suppressive effect. Proteomic analysis of secreted proteins from EU07 and FZB24 revealed the presence of lytic enzymes, cellulases, proteases, 1,4-b-glucanase and hydrolases, all of which contribute to degradation of the pathogen cell wall. Further proteomic investigations showed that proteins involved in metabolism, protein folding, protein degradation, translation, recognition and signal transduction cascade play an important role in the control of Fusarium oxysporum. Our findings provide new knowledge on the mechanism of action of Bacillus species and insight into biocontrol mechanisms. [ABSTRACT FROM AUTHOR]

DRAM is a lysosomal membrane protein and is critical for p53-mediated autophagy and apoptosis. DRAM has a potential tumor-suppressive function and is downregulated in many human cancers. However, the regulation of DRAM expression is poorly described so far. Here, we demonstrated that serum deprivation strongly induces DRAM expression in liver cancer cells and a core DNA sequence in the DRAM promoter is essential for its responsiveness to serum deprivation. We further observed that euchromatin markers for active transcriptions represented by diacetyl-H3, tetra-acetyl-H4 and the trimethyl- H3K4 at the core promoter region of DRAM gene are apparently increased in a time-dependent manner upon serum deprivation, and concomitantly the dimethyl-H3K9, a herterochromatin marker associated with silenced genes, was timedependently decreased. Moreover, the chromatin remodeling factor Brg-1 is enriched at the core promoter region of the DRAM gene and is required for serum deprivation induced DRAM expression. These observations lay the ground for further investigation of the DRAM gene expression. [ABSTRACT FROM AUTHOR]

Background: Nitrilase is an important member of the nitrilase superfamiliy. It has attracted substantial interest from academia and industry for its function of converting nitriles directly into the corresponding carboxylic acids in recent years. Thus nitrilase has played a crucial role in production of commercial carboxylic acids in chemical industry and detoxification of nitrile-contaminated wastes. However, conventional studies mainly focused on the bacterial nitrilase and the potential of fungal nitrilase has been far from being fully explored. Research on fungal nitrilase gene expression will advance our understanding for its biological function of fungal nitrilase in nitrile hydrolysis. Methodology/Principal Findings: A fungal nitrilase gene from Gibberella intermedia was cloned through reverse transcription-PCR. The open reading frame consisted of 963 bp and potentially encoded a protein of 320 amino acid residues with a theoretical molecular mass of 35.94 kDa. Furthermore, the catalytic triad (Glu-45, Lys-127, and Cys-162) was proposed and confirmed by site-directed mutagenesis. The encoding gene was expressed in Escherichia coli Rosetta-gami (DE3) and the recombinant protein with His6-tag was purified to electrophoretic homogeneity. The purified enzyme exhibited optimal activity at 45°C and pH 7.8. This nitrilase was specific towards aliphatic and aromatic nitriles. The kinetic parameters Vmax and Km for 3-cyanopyridine were determined to be 0.81 µmol/min·mg and 12.11 mM through Hanes-Woolf plot, respectively. 3-Cyanopyridine (100 mM) could be thoroughly hydrolyzed into nicotinic acid within 10 min using the recombinant strain with the release of about 3% nicotinamide and no substrate was detected. Conclusions/Significance: In the present study, a fungal nitrilase was cloned from the cDNA sequence of G. intermedia and successfully expressed in E. coli Rosetta-gami (DE3). The recombinant strain displayed good 3-cyanopyridine degradation efficiency and wide substrate spectrum. This fungal nitrilase might be a potential candidate for industrial applications in carboxylic acids production. [ABSTRACT FROM AUTHOR]

To gain insights into the protein dynamics during seed development, a proteomic study on the developing Brassica campestri L. seeds with embryos in different embryogenesis stages was carried out. The seed proteins at 10, 16, 20, 25 and 35 DAP (days after pollination), respectively, were separated using two-dimensional gel electrophoresis and identities of 209 spots with altered abundance were determined by matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF MS). These proteins were classified into 16 groups according to their functions. The most abundant proteins were related to primary metabolism, indicating the heavy demand of materials for rapid embryo growth. Besides, the high amount of proteins involved in protein processing and destination indicated importance of protein renewal during seed development. The remaining were those participated in oxidation/detoxification, energy, defense, transcription, protein synthesis, transporter, cell structure, signal transduction, secondary metabolism, transposition, DNA repair, storage and so on. Protein abundance profiles of each functional class were generated and hierarchical cluster analysis established 8 groups of dynamic patterns. Our results revealed novel characters of protein dynamics in seed development in Brassica campestri L. and provided valuable information about the complex process of seed development in plants. [ABSTRACT FROM AUTHOR]

Background: HIV infection related to commercial sexual contact is a serious public health issue in China. The objectives of the present study are to explore the predictors of condom use among female sex workers (FSWs) in China and examine the relationship between Health Belief Model (HBM) constructs. Methodology/Principal Findings: A cross-sectional study was conducted in two cities (Wuhan and Suizhou) in Hubei Province, China, between July 2009 and June 2010. A total of 427 FSWs were recruited through mediators from the 'low-tier' entertainment establishments. Data were obtained by self-administered questionnaires. Structural equation models were constructed to examine the association. We collected 363 valid questionnaires. Within the context of HBM, perceived severity of HIV mediated through perceived benefits of condom use had a weak effect on condom use (r = 0.07). Perceived benefits and perceived barriers were proximate determinants of condom use (r = 0.23 and r =20.62, respectively). Self-efficacy had a direct effect on perceived severity, perceived benefits, and perceived barriers, which was indirectly associated with condom use behaviors (r = 0.36). Conclusions/Significance: The HBM provides a useful framework for investigating predictors of condom use behaviors among FSWs. Future HIV prevention interventions should focus on increasing perceived benefits of condom use, reducing barriers to condoms use, and improving self-efficacy among FSWs. [ABSTRACT FROM AUTHOR]

We investigated the expression status of periostin in breast cancer stem cells and its clinical implications in order to lay a foundation for managing breast cancer. CD44+/CD242/line- tumor cells (CSC) from clinical specimens were sorted using flow cytometry. Periostin expression status was detected in CSC cells and 1,086 breast cancer specimens by Western blot and immunohistochemistry staining, with the CSC ratio determined by immunofluorescence double staining. The relationship between the periostin protein and clinico-pathological parameters and prognosis was subsequently determined. As a result, CSC cells are more likely to generate new tumors in mice and cell microspheres that are deficient in NOD/SCID compared to the control group. Periostin protein was expressed higher in CSC cells compared to the control cells and was found to be related to CSC chemotherapy resistance. Moreover, periostin expression was found to be related to the CSC ratio in 1,086 breast cancer specimens (P = 0.001). In total, 334 (30.76%) of the 1,086 breast cases showed high periostin expression. After universal and Spearman regression correlation analysis, periostin was observed to be related to histological grade, CSC ratio, lymph node metastasis, tumor size, and triple-negative breast cancer (all P<0.05). Furthermore, periostin was shown to attain a significantly more distant bone metastasis and worse disease-specific survival than those with none or low-expressed periostin protein (P = 0.001). In the Cox regression test, periostin protein was detected as an independent prognostic factor (P = 0.001). In conclusion, periostin was found to be related to the CSC and an independent prognostic factor for breast cancer. It is also perhaps a potential target to breast cancer. [ABSTRACT FROM AUTHOR]

Background: Dietary factors play an important role in glycemic control in diabetic patients. However, little is known about their effects among Chinese diabetic patients, whose diets are typically abundant in fiber and high in glycemic index (GI) values. Methodology/Principal Findings: 934 patients with type 2 diabetes and 918 healthy volunteers from Pudong New Area, Shanghai, China, were interviewed during the period of Oct-Dec, 2006 to elicit demographic characteristics and lifestyle factors. Dietary habits were assessed using a validated food frequency questionnaire. Anthropometric measurements, bio- specimen collection and biochemical assays were conducted at the interview according to a standard protocol. In this population, diabetic patients consumed lower levels of energy and macronutrients but had higher levels of fasting plasma glucose (FPG), glycolated hemoglobin A1c (HbA1c), triglyceride and body mass index than healthy adults. While the average consumption levels of the nutrients among diabetic patients did not vary along duration of the disease, the average levels of FPG and HbA1c increased with increasing duration. Regardless of diabetes duration, HbA1c level was observed lower in patients having a higher fiber or lower GI intake. Compared with those with the lowest tertile intake of fiber, the adjusted odds ratios (ORs) for poor glycemic control reduced from 0.75 (95%CI: 0.54--1.06) to 0.51 (95%CI: 0.34--0.75) with increasing tertile intake (P for trend <0.001). Conclusions: Dietary fiber may play an important role in reducing HbA1c level. Increasing fiber intake may be an effective approach to improve glycemic control among Chinese diabetic patients. [ABSTRACT FROM AUTHOR]

Angiogenesis is a prerequisite for the formation and development of endometriosis. Pigment epithelium derived factor (PEDF) is a natural inhibitor of angiogenesis. We previously demonstrated a reduction of PEDF in the peritoneal fluid, serum and endometriotic lesions from women with endometriosis compared with women without endometriosis. Here, we aim to investigate the inhibitory effect of PEDF on human endometriotic cells in vivo and in vitro. We found that PEDF markedly inhibited the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro by up-regulating PEDF expression and down-regulating vascular endothelial growth factor (VEGF) expression. Moreover, apoptotic index was significantly increased in endometriotic lesions in vivo and endometriotic stromal cells in vitro when treated with PEDF. In mice treated with PEDF, decreased microvessel density labeled by Von Willebrand factor but not by α-Smooth Muscle Actin was observed in endometriotic lesions. And it showed no increase in PEDF expression of the ovary and uterus tissues. These findings suggest that PEDF gene therapy may be a new treatment for endometriosis. [ABSTRACT FROM AUTHOR]

Background: Myofibroblast differentiation, characterized by α-smooth muscle actin (α-SMA) expression, is a key process in organ fibrosis, and is induced by TGF-β. Here we examined whether an anti-fibrotic agent, N-acetyl-seryl-aspartyl-lysylproline (Ac-SDKP), can regulate induction of TGF-β signaling and myofibroblast differentiation as a potential key component of its anti-fibrotic mechanism in vivo and in vitro. Methodology/Principal Findings: Rat pulmonary fibroblasts were cultured in vitro and divided to 4 groups 1) control; 2) TGF-β1; 3) TGF-β1+ LY364947; 4) TGF-β1+Ac-SDKP. For in vivo studies, six groups of animals were utilized 1) control 4w; 2) silicotic 4w; 3) control 8w; 4) silicotic 8w; 5) Ac-SDKP post-treatment; 6)Ac-SDKP pre-treatment. SiO2 powders were douched in the trachea of rat to make the silicotic model. Myofibroblast differentiation was measured by examining expression of α-SMA, as well as expression of serum response factor (SRF), a key regulator of myofibroblast differentiation. The expressions of collagen, TGF-β1 and RAS signaling were also assessed. The results revealed that TGF-β1 strongly induced myofibroblast differentiation and collagen synthesis in vitro, and that pre-treatment with Ac-SDKP markedly attenuated myofibroblast activation, as well as induction of TGF-β1 and its receptor. Similar results were observed in vivo in the pathologically relevant rat model of silicosis. Ac-SDKP treatment in vivo strongly attenuated 1) silicosis-induced increased expressions of TGF-β1 and RAS signaling, 2) myofibroblast differentiation as indicated by a robust decrease of SRF and α-SMA-positive myofibroblast localization in siliconic nodules in the lung, 3) collagen deposition. Conclusion/Significance: The results of the present study suggest a novel mechanism of action for Ac-SDKP's beneficial effect in silicosis, which involves attenuation of TGF-β1 and its receptors, SRF and Ang II type 1 receptor (AT1) expression, collagen deposition and myofibroblast differentiation. The results further suggest that therapies targeting myofibroblast differentiation may have therapeutic efficacy in treatment of silicosis of the lung [ABSTRACT FROM AUTHOR]

NMD3 is required for nuclear export of the 60S ribosomal subunit in yeast and vertebrate cells, but no corresponding function of NMD3 has been reported in plants. Here we report that Arabidopsis thaliana NMD3 (AtNMD3) showed a similar function in the nuclear export of the 60S ribosomal subunit. Interference with AtNMD3 function by overexpressing a truncated dominant negative form of the protein lacking the nuclear export signal sequence caused retainment of the 60S ribosomal subunits in the nuclei. More interestingly, the transgenic Arabidopsis with dominant negative interference of AtNMD3 function showed a striking failure of secondary cell wall thickening, consistent with the altered expression of related genes and composition of cell wall components. Observation of a significant decrease of rough endoplasmic reticulum (RER) in the differentiating interfascicular fiber cells of the transgenic plant stems suggested a link between the defective nuclear export of 60S ribosomal subunits and the abnormal formation of the secondary cell wall. These findings not only clarified the evolutionary conservation of NMD3 functions in the nuclear export of 60S ribosomal subunits in yeast, animals and plants, but also revealed a new facet of the regulatory mechanism underlying secondary cell wall thickening in Arabidopsis. This new facet is that the nuclear export of 60S ribosomal subunits and the formation of RER may play regulatory roles in coordinating protein synthesis in cytoplasm and transcription in nuclei. [ABSTRACT FROM AUTHOR]

Rice (Oryza sativa) is an excellent model monocot with a known genome sequence for studying embryogenesis. Here we report the transcriptome profiling analysis of rice developing embryos using RNA-Seq as an attempt to gain insight into the molecular and cellular events associated with rice embryogenesis. RNA-Seq analysis generated 17,755,890 sequence reads aligned with 27,190 genes, which provided abundant data for the analysis of rice embryogenesis. A total of 23,971, 23,732, and 23,592 genes were identified from embryos at three developmental stages (3-5, 7, and 14 DAP), while an analysis between stages allowed the identification of a subset of stage-specific genes. The number of genes expressed stagespecifically was 1,131, 1,443, and 1,223, respectively. In addition, we investigated transcriptomic changes during rice embryogenesis based on our RNA-Seq data. A total of 1,011 differentially expressed genes (DEGs) (log2Ratio ≥1, FDR ≤0.001) were identified; thus, the transcriptome of the developing rice embryos changed considerably. A total of 672 genes with significant changes in expression were detected between 3-5 and 7 DAP; 504 DEGs were identified between 7 and 14 DAP. A large number of genes related to metabolism, transcriptional regulation, nucleic acid replication/processing, and signal transduction were expressed predominantly in the early and middle stages of embryogenesis. Protein biosynthesisrelated genes accumulated predominantly in embryos at the middle stage. Genes for starch/sucrose metabolism and protein modification were highly expressed in the middle and late stages of embryogenesis. In addition, we found that many transcription factor families may play important roles at different developmental stages, not only in embryo initiation but also in other developmental processes. These results will expand our understanding of the complex molecular and cellular events in rice embryogenesis and provide a foundation for future studies on embryo development in rice and other cereal crops. [ABSTRACT FROM AUTHOR]

Introduction: Hip OF carries the highest morbidity and mortality. Previous studies revealed that individual genes/loci in the Tumor Necrosis Factor (TNF) -Related Apoptosis-Inducing Ligand (TRAIL) pathway were associated with bone metabolism. This study aims to verify the potential association between hip OF and TRAIL pathway. Methods: Using genome-wide genotype data from Affymetrix 500 K SNP arrays, we performed novel pathway-based association analyses for hip OF in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). Results: The TRAIL pathway achieved a significant p value (p = 0.01) for association with hip OF. Among the 38 genes in the TRAIL pathway, seven genes achieved nominally significant association with hip OF (p<0.05); the TNFSF10 (TRAIL) gene obtained the most significant p value (p = 1.70x10-4). SNPs (rs719126, rs6533015, rs9594738, rs1805034, rs11160706) from five genes (CFLAR, NFKB1, TNFSF11, TNFRSF11A, TRAF3) of the pathway had minor alleles that appear to be protective to hip OF. SNPs (rs6445063 and rs4259415) from two genes (TNFSF10 and TNFRSF10B) of the pathway had minor alleles (A) that are associated with an increased risk of hip OF, with the ORs (odds ratios) of 16.51 (95%CI:3.83-71.24) and 1.37 (95%CI:1.08- 1.74), respectively. Conclusions: Our study supports the potential role of the TRAIL pathway in the pathogenesis of hip OF in Chinese Han population. Further functional study of this pathway will be pursued to determine the mechanism by which it confers risk to hip OF. [ABSTRACT FROM AUTHOR]

Multigenic traits are very common in plants and cause diversity. Nutritional quality is such a trait, and one of its factors is the composition and relative expression of storage protein genes. In maize, they represent a medium-size gene family distributed over several chromosomes and unlinked locations. Two inbreds, B73 and BSSS53, both from the Iowa Stiff Stock Synthetic collection, have been selected to analyze allelic and non-allelic variability in these regions that span between 80-500 kb of chromosomal DNA. Genes were copied to unlinked sites before and after allotetraploidization of maize, but before transposition enlarged intergenic regions in a haplotype-specific manner. Once genes are copied, expression of donor genes is reduced relative to new copies. Epigenetic regulation seems to contribute to silencing older copies, because some of them can be reactivated when endosperm is maintained as cultured cells, indicating that copy number variation might contribute to a reserve of gene copies. Bisulfite sequencing of the promoter region also shows different methylation patterns among gene clusters as well as differences between tissues, suggesting a possible position effect on regulatory mechanisms as a result of inserting copies at unlinked locations. The observations offer a potential paradigm for how different gene families evolve and the impact this has on their expression and regulation of their members. [ABSTRACT FROM AUTHOR]

Background: Environmental stress can accelerate the directional selection and evolutionary rate of specific stress-response proteins to bring about new or altered functions, enhancing an organism's fitness to challenging environments. Plateau pika (Ochotona curzoniae), an endemic and keystone species on Qinghai-Tibetan Plateau, is a high hypoxia and low temperature tolerant mammal with high resting metabolic rate and non-shivering thermogenesis to cope in this harsh plateau environment. Leptin is a key hormone related to how these animals regulate energy homeostasis. Previous molecular evolutionary analysis helped to generate the hypothesis that adaptive evolution of plateau pika leptin may be driven by cold stress. Methodology/Principal Findings: To test the hypothesis, recombinant pika leptin was first purified. The thermogenic characteristics of C57BL/6J mice injected with pika leptin under warm (23±1°C) and cold (5±1°C) acclimation is investigated. Expression levels of genes regulating adaptive thermogenesis in brown adipose tissue and the hypothalamus are compared between pika leptin and human leptin treatment, suggesting that pika leptin has adaptively and functionally evolved. Our results show that pika leptin regulates energy homeostasis via reduced food intake and increased energy expenditure under both warm and cold conditions. Compared with human leptin, pika leptin demonstrates a superior induced capacity for adaptive thermogenesis, which is reflected in a more enhanced b-oxidation, mitochondrial biogenesis and heat production. Moreover, leptin treatment combined with cold stimulation has a significant synergistic effect on adaptive thermogenesis, more so than is observed with a single cold exposure or single leptin treatment. Conclusions/Significance: These findings support the hypothesis that cold stress has driven the functional evolution of plateau pika leptin as an ecological adaptation to the Qinghai-Tibetan Plateau. [ABSTRACT FROM AUTHOR]

Background: Limited information is available regarding mechanisms by which miRNAs contribute to pulmonary carcinogenesis. The present study was undertaken to examine expression and function of miRNAs induced by cigarette smoke condensate (CSC) in normal human respiratory epithelia and lung cancer cells. Methodology: Micro-array and quantitative RT-PCR (qRT-PCR) techniques were used to assess miRNA and host gene expression in cultured cells, and surgical specimens. Software-guided analysis, RNA cross-link immunoprecipitation (CLIP), 3′ UTR luciferase reporter assays, qRT-PCR, focused super-arrays and western blot techniques were used to identify and confirm targets of miR-31. Chromatin immunoprecipitation (ChIP) techniques were used to evaluate histone marks and transcription factors within the LOC554202 promoter. Cell count and xenograft experiments were used to assess effects of miR-31 on proliferation and tumorigenicity of lung cancer cells. Results: CSC significantly increased miR-31 expression and activated LOC554202 in normal respiratory epithelia and lung cancer cells; miR-31 and LOC554202 expression persisted following discontinuation of CSC exposure. miR-31 and LOC554202 expression levels were significantly elevated in lung cancer specimens relative to adjacent normal lung tissues. CLIP and reporter assays demonstrated direct interaction of miR-31 with Dickkopf-1 (Dkk-1) and DACT-3. Over-expression of miR-31 markedly diminished Dkk-1 and DACT3 expression levels in normal respiratory epithelia and lung cancer cells. Knock-down of miR-31 increased Dkk-1 and DACT3 levels, and abrogated CSC-mediated decreases in Dkk-1 and DACT-3 expression. Furthermore, over-expression of miR-31 diminished SFRP1, SFRP4, and WIF-1, and increased Wnt-5a expression. CSC increased H3K4Me3, H3K9/14Ac and C/EBP-β levels within the LOC554202 promoter. Knock-down of C/EBP-β abrogated CSC-mediated activation of LOC554202. Over-expression of miR-31 significantly enhanced proliferation and tumorigenicity of lung cancer cells; knock-down of miR-31 inhibited growth of these cells. Conclusions: Cigarette smoke induces expression of miR-31 targeting several antagonists of cancer stem cell signaling in normal respiratory epithelia and lung cancer cells. miR-31 functions as an oncomir during human pulmonary carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: In March 2009, pandemic influenza A(H1N1) (A(H1N1)pdm) emerged in Mexico and the United States. In Japan, since the first outbreak of A(H1N1)pdm in Osaka and Hyogo Prefectures occurred in the middle of May 2009, the virus had spread over 16 of 47 prefectures as of June 4, 2009. Methods/Principal Findings: We analyzed all-segment concatenated genome sequences of 75 isolates of A(H1N1)pdm viruses in Japan, and compared them with 163 full-genome sequences in the world. Two analyzing methods, distancebased and Bayesian coalescent MCMC inferences were adopted to elucidate an evolutionary relationship of the viruses in the world and Japan. Regardless of the method, the viruses in the world were classified into four distinct clusters with a few exceptions. Cluster 1 was originated earlier than cluster 2, while cluster 2 was more widely spread around the world. The other two clusters (clusters 1.2 and 1.3) were suggested to be distinct reassortants with different types of segment assortments. The viruses in Japan seemed to be a multiple origin, which were derived from approximately 28 transported cases. Twelve cases were associated with monophyletic groups consisting of Japanese viruses, which were referred to as micro-clade. While most of the micro-clades belonged to the cluster 2, the clade of the first cases of infection in Japan originated from cluster 1.2. Micro-clades of Osaka/Kobe and the Fukuoka cases, both of which were school-wide outbreaks, were eradicated. Time of most recent common ancestor (tMRCA) for each micro-clade demonstrated that some distinct viruses were transmitted in Japan between late May and early June, 2009, and appeared to spread nation-wide throughout summer. Conclusions: Our results suggest that many viruses were transmitted from abroad in late May 2009 irrespective of preventive actions against the pandemic influenza, and that the influenza A(H1N1)pdm had become a pandemic stage in June 2009 in Japan. [ABSTRACT FROM AUTHOR]

Osteoporosis is a major public health problem. It is mainly characterized by low bone mineral density (BMD) and/or lowtrauma osteoporotic fractures (OF), both of which have strong genetic determination. The specific genes influencing these phenotypic traits, however, are largely unknown. Using the Affymetrix 500K array set, we performed a case-control genomewide association study (GWAS) in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip OF and 516 controls. We found that a SNP, rs13182402 within the ALDH7A1 gene on chromosome 5q31, was strongly associated with OF with evidence combined GWAS and replication studies (P = 2.08610-9, odds ratio = 2.25). In order to explore the target risk factors and potential mechanism underlying hip OF risk, we further examined this candidate SNP's relevance to hip BMD both in Chinese and Caucasian populations involving 9,962 additional subjects. This SNP was confirmed as consistently associated with hip BMD even across ethnic boundaries, in both Chinese and Caucasians (combined P = 6.39610-6), further attesting to its potential effect on osteoporosis. ALDH7A1 degrades and detoxifies acetaldehyde, which inhibits osteoblast proliferation and results in decreased bone formation. Our findings may provide new insights into the pathogenesis of osteoporosis. [ABSTRACT FROM AUTHOR]

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease. [ABSTRACT FROM AUTHOR]

Background. Environmental stress can accelerate the evolutionary rate of specific stress-response proteins and create new functions specialized for different environments, enhancing an organism’s fitness to stressful environments. Pikas (order Lagomorpha), endemic, non-hibernating mammals in the modern Holarctic Region, live in cold regions at either high altitudes or high latitudes and have a maximum distribution of species diversification confined to the Qinghai-Tibet Plateau. Variations in energy metabolism are remarkable for them living in cold environments. Leptin, an adipocyte-derived hormone, plays important roles in energy homeostasis. Methodology/Principal Findings. To examine the extent of leptin variations within the Ochotona family, we cloned the entire coding sequence of pika leptin from 6 species in two regions (Qinghai-Tibet Plateau and Inner Mongolia steppe in China) and the leptin sequences of plateau pikas (O. curzonia) from different altitudes on Qinghai-Tibet Plateau. We carried out both DNA and amino acid sequence analyses in molecular evolution and compared modeled spatial structures. Our results show that positive selection (PS) acts on pika leptin, while nine PS sites located within the functionally significant segment 85-119 of leptin and one unique motif appeared only in pika lineages-the ATP synthase α and β subunit signature site. To reveal the environmental factors affecting sequence evolution of pika leptin, relative rate test was performed in pikas from different altitudes. Stepwise multiple regression shows that temperature is significantly and negatively correlated with the rates of non-synonymous substitution (Ka) and amino acid substitution (Aa), whereas altitude does not significantly affect synonymous substitution (Ks), Ka and Aa. Conclusions/Significance. Our findings support the viewpoint that adaptive evolution may occur in pika leptin, which may play important roles in pikas’ ecological adaptation to extreme environmental stress. We speculate that cold, and probably not hypoxia, may be the primary environmental factor for driving adaptive evolution of pika leptin. [ABSTRACT FROM AUTHOR]

Background: The androgen receptor (AR) plays important roles in the development of male phenotype and in different human diseases including prostate cancers. The AR can act either as a promoter or a tumor suppressor depending on cell types. The AR proliferative response program has been well studied, but its prohibitive response program has not yet been thoroughly studied., Methodology/principal Findings: Previous studies found that PC3 cells expressing the wild-type AR inhibit growth and suppress invasion. We applied expression profiling to identify the response program of PC3 cells expressing the AR (PC3-AR) under different growth conditions (i.e. with or without androgens and at different concentration of androgens) and then applied the newly developed ChIP-seq technology to identify the AR binding regions in the PC3 cancer genome. A surprising finding was that the comparison of MOCK-transfected PC3 cells with AR-transfected cells identified 3,452 differentially expressed genes (two fold cutoff) even without the addition of androgens (i.e. in ethanol control), suggesting that a ligand independent activation or extremely low-level androgen activation of the AR. ChIP-Seq analysis revealed 6,629 AR binding regions in the cancer genome of PC3 cells with an FDR (false discovery rate) cut off of 0.05. About 22.4% (638 of 2,849) can be mapped to within 2 kb of the transcription start site (TSS). Three novel AR binding motifs were identified in the AR binding regions of PC3-AR cells, and two of them share a core consensus sequence CGAGCTCTTC, which together mapped to 27.3% of AR binding regions (1,808/6,629). In contrast, only about 2.9% (190/6,629) of AR binding sites contains the canonical AR matrix M00481, M00447 and M00962 (from the Transfac database), which is derived mostly from AR proliferative responsive genes in androgen dependent cells. In addition, we identified four top ranking co-occupancy transcription factors in the AR binding regions, which include TEF1 (Transcriptional enhancer factor), GATA (GATA transcription factors), OCT (octamer transcription factors) and PU1 (PU.1 transcription factor)., Conclusions/significance: Our data provide a valuable data set in understanding the molecular basis for growth inhibition response program of the AR in prostate cancer cells, which can be exploited for developing novel prostate cancer therapeutic strategies.